This invention relates to a composition and method for producing palatable drug granules suitable for use in the development of pharmaceutical dosage forms. Specifically, this invention relates to the entrapment of drugs using a combination of polymer ingredients, and especially polyvinylpyrrolidone (PVP) and polyvinyl acetate phthalate (PVAP).
For many people, taking medicine can be a very unpleasant experience. Tablets are the most commonly and widely used dosage form. Most tablet products are designed to be swallowed whole. This poses a serious problem in children and elderly patients who have difficulty swallowing. In addition, the drugs used in the tablets often have an offending taste.
Crushing of such tablets, for ease of swallowing, can cause significant changes in the bioavailability of the drug and may irritate the mucous membranes of the esophagus and stomach. Further, drugs sensitive to gastric fluids may degrade, or react with the gastric milieu, and produce potentially harmful byproducts.
Chewable tablets and liquids provide alternatives for people who are unable or unwilling to swallow pills. In most cases, however, chewable tablets and liquids are just as unpleasant tasting as pills. This makes it especially difficult for convincing small children to take their medicine, which is problematic if the medicine is necessary to treat an infection or other illness.
Chewable tablets are intended to be masticated in the mouth before swallowing. Thus, it must impart good flavor and mouth-feel. This presents a challenge to a formulator if the drug to be used is bitter in taste. Conventional methods of taste masking of such drugs with sweeteners or commonly used flavoring agents have not proven to be adequate, however.
To overcome this problem, several drug coating methods have been developed. Sugar coating is regarded as the oldest method for masking the taste of drug particles, and involves the deposition of sucrose using an aqueous solution. Sugar-coating has the disadvantages of requiring large quantities of coating material to be applied, and nonuniform distribution of the coating material. In addition, sugar coatings are generally not adequate to alleviate the foul taste of the medication.
Other taste-masking methods include: (a) coating of drug particles with a taste-neutral polymer by spray-drying, wet granulation, fluidized bed, and microencapsulation; (b) coating with molten waxes of a mixture of molten waxes and other pharmaceutical adjuvants; (c) entrapment of drug particles by complexation, flocculation or coagulation of an aqueous polymeric dispersion; (d) preparation of drug-cyclodextrin inclusion complexes; (e) adsorption of drug particles on resin and inorganic supports, and (f) solid dispersion methods wherein a drug and one or more taste neutral compounds are melted and cooled, or co-precipitated by a solvent evaporation technique. While these methods claim to have alleviated the deficiencies associated with taste-masking, there is a need in the art for a means of producing pharmaceutical products that overcomes the taste of bitter drugs.
Polymers have been used in the design and development of pharmaceutical products in order to modify the release pattern of the drug. Sustained or controlled release products are primarily developed to extend the release of a drug over a long period of time. Such preparations eliminate the need for multiple dosage regimens, especially for drugs requiring reasonably constant blood levels over a long period of time. Sustained release formulations have also been used frequently with drugs where rapid release is likely to cause undesirable side effects, such as the ulceration of the stomach commonly associated with potassium chloride and non-steroidal anti-inflammatory drugs. Other materials that have been commonly used in the manufacture of sustained released formulations include mixtures of waxes, shellac, etc.
It is not uncommon to use two or more polymers in a pharmaceutical preparation to develop a pharmaceutically acceptable product. However, the varied structure and chemistry of various polymers may render ample opportunity for them to undergo physical and/or chemical interaction in situ. Such interactions greatly influence product stability, modify drug release kinetics, alter drug bioavailability, and/or pose safety concerns.
For example, Satoh et al. Factors affecting the bioadhesive property of tablets consisting of hydroxypropyl cellulose and carboxyvinyl polymer. Chem. Pharm. Bull., 37, 1366-1368 (1989) reported that the use of a 3:2 weight ratio of hydroxylpropylcellulose (HPC) and carboxylvinyl polymer (CP) as excipients in tablets significantly decreased the bioadhesion force and greatly affected the drug release. Similar effects were noted by Takayama et al. Effect of interpolymer complex formation on bioadhesive property and drug release phenomenon of compressed tablet consisting of chitosan and sodium hyaluronate. Chem. Pharm. Bull., 38, 1993-1997 (1990) with compressed tablets prepared using chitosan and sodium hyaluronate. Tablets prepared using chitosan alone exhibited weak bioadhesive strength, whereas sodium hyaluronate and chitosan produced tablets with strong adhesive forces. The release of brilliant blue varied with the weight ratios of the two polymers, suggesting the occurrence of an interaction between sodium hyaluronate and chitosan.
Recently, the interaction of CP with HPC and sodium carboxymethylcellulose (NaCMC) and its effects on the bioadhesive strength and the release of verapamil was reported (Gupta et al., Interpolymer complexation and its effect on bioadhesive strength and dissolution characteristics of buccal drug delivery. Drug Dev. Ind. Pharm., 20, 315-325 (1994)). CP reportedly formed a stronger complex with HPC than with NaCMC.
Polyvinylpyrrolidone (PVP) is a water soluble, physiologically inert polyamide polymer. It exhibits unusual colloidal and complexing properties, and has been extensively used in pharmacy for various purposes.
Elgindy and Elegakey "Parenopenst"Carbopol-polyvinypyrrolidone flocculation. Sci. Pharm., 49, 427-434 (1981"Parenclosest" and Elegakey and Elgindy "Parenopenst"Drug encapsulation by carbopol-polyvinylpyrrolidone flocculation technique, Sci. Pharm., 49, 434-441 (1981) prepared PVP-polyacrylic acid (Carbopol 934, 940, and 941) complexes and demonstrated their use in the development of sustained release drug products.
Further, Takayama and Nagai, Application of interpolymer complexation of polyvinylpyrrolidone/carboxyvinyl polymer to control of drug release. Chem. Pharm. Bull, 35, 4921-4927 (1987), reported that PVP forms a 1:1 complex with carboxyvinyl polymer. Recently, Gupta et al., Interpolymer complexation and its effect on bioadhesive strength and dissolution characteristics of buccal drug delivery. Drug Dev. Ind. Pharm., 20, 315-325 (1994)) reinvestigated the interaction between Carbopol 934 and PVP. The degree of complexation was found to be higher at low acidic conditions, and decreased with increasing pH of the solution. Compared to the parent polymers, the complex exhibited increased bioadhesive strength and decreased drug release rates.
More recently, Bell and Peppas, Swelling/syneresis phenomena in gel-forming interpolymer complexes. J. Biomater. Sci., Polym. Ed., 7, 671-83 (1996) studied the interaction of poly(methacrylic acid)(PMMA) with polyethylene glycol. They reported that complexation occurred at pH low enough to protonate the acid of PMMA. At high pH, the acid group becomes neutralized and, consequently, no complexation occurs.
While it has been known that PVP forms complexes with many substances, it was not known in the art that PVP reacts and forms a complex with polyvinyl acetate phthalate (PVAP), methacrylic acid-alkylmethacrylate copolymers (where alkyl=methyl, ethyl, etc.), and other acrylic and nonacrylic polymers having at least one free carboxylic group. The present inventor has now discovered that PVP readily reacts with PVAP, methacrylic acid-alkylmethacrylate copolymers (where alkyl=methyl, ethyl, etc.), and other acrylic and nonacrylic polymers having at least one free carboxylic group to form an insoluble complex. This complex can be used to produce highly palatable granules for bitter tasting drugs, and further serves as a sustained release effector.
Accordingly, it is a primary objective of the present invention to provide a composition and method for entrapping bitter-tasting drugs that results in a pharmaceutical dosage form that is palatable.
It is a further objective of the present invention to provide a composition and method for producing palatable granules of bitter-tasting drugs that provides a good mouth feel.
It is still a further objective of the present invention to provide a composition and method for entrapment of bitter-tasting drugs that may be used to prepare oral dosage forms, including tablets, chewable tablets, and suspensions.
It is yet a further objective of the present invention to provide a composition and method for preparing granules of bitter-tasting drugs which may be used to produce a sustained release product.
It is still a further objective of the present invention to provide a composition and method for the manufacture of palatable granules of bitter-tasting drugs which is cost-effective.
The method and means of accomplishing each of the above objectives as well as others will become apparent from the detailed description of the invention which follows hereafter.
The invention describes a method and composition for entrapping drugs that are bitter-tasting and/or require sustained-release properties. It uses an amorphous polymer complex consisting of PVAP, methacrylic acid-alkylmethacrylate copolymers (where alkyl=methyl, ethyl, etc.), or an acrylic or nonacrylic polymer having at least one free carboxylic group and polyvinylpyrrolidone (PVP) that is insoluble in acidic pH solutions or organic solvents in which the parent polymers dissolve. The entrapment is achieved by in situ complexation between the polymers in an organic solvent or acidic aqueous solution.
The in situ complexation between the polymers entraps the bitter tasting drug, providing a highly palatable powder dosage form that effectively eliminates the bitter taste of the drug and provides a good mouth-feel. The entrapment further provides a slower release profile for the encapsulated drug, thereby resulting in a sustained release dosage form. The palatable drug granules of this invention may be used to produce other oral dosage forms including tablets, effervescent tablets, chewable tablets and suspensions. Palatable powder, effervescent tablet, chewable tablet, and suspension dosage forms are an ideal alternative for geriatric, pediatric, and other patients who must take several pills a day.